3. The Clinical Management Protocols Leukaemia s (09-7A-115)

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1 3. The Clinical Management Protocols Leukaemia s (09-7A-115) These guidelines are for use within the SY&H CCN for treatment of haematological malignancies (excluding lymphoma) in children and young persons below the age of 16 years. The authors accept no responsibility for their use for any other purpose. The guidance indicates which treatment protocol to use for specific malignancies and where to find further information. The specific treatment regimens and protocols should be consulted before commencing an individual patient s treatment. INTRODUCTION These guidelines were agreed by consensus by the paediatric haematologists at SCH and have been reviewed by the paediatric oncology pharmacist. They are adapted from the following national trial protocols or guidelines on the management of children with haematological malignancies which are available on the H drive in clinical trials and treatment guidelines folders: Acute Lymphoblastic Leukaemia. (ALL) ALL interim guidelines (Protocol on file) UKALL 2011 (Protocol on file) Ph-pos ALL guideline (Protocol on file) Acute Myeloid Leukaemia (AML) AML Interim guideline (Protocol on file) Infant Acute Lymphoblastic Leukaemia Interfant 06 (Protocol on file). Down syndrome AML Aplastic Anaemia Chronic Myeloproliferative Disorders Adult-type Chronic myeloid leukaemia (CML) Acute Promyelocytic Leukaemia (APL) Myelodysplasia Haemophagocytic lymphocytic histiocytosis (HLH) Guidelines for these rare sub-types are on file and can be downloaded by CCLG members from the guidelines section of Further guideline on aplastic anaemia can be found on the BCSH guideline site at Background Leukaemia is the single most common cause of childhood cancer representing a third of all cases. Around 80% of patients have Acute Lymphoblastic Leukaemia (ALL), 15% Acute Myeloid Leukaemia (AML) and the remainder are made up of Juvenile Myelomonocytic Leukaemia (JMML), adult type Ph-pos Chronic Myeloid Leukaemia (AT-CML), various subtypes of Myelodysplasia ( MDS) and secondary or treatment-related leukaemia. Survival of children with leukaemia has improved dramatically over the last few decades. With modern first line therapy, children with ALL should expect an 85% chance of cure and SC(NHS)FT 2017 Page 1 of 15

2 those with AML around 60%. The outlook for rarer forms such as JMML, AT-CML and MDS has also improved due to a reduction in transplant-related mortality such that around 60-80% of these patients can expect to be cured. Treatment of ALL and AML depends on a variety of prognostic factors including phenotypic and genotypic sub-type, age and presenting features. The specific variables employed in risk stratification have evolved in the light of new research and the algorithms in use at any given time are part of ongoing national trials. Referral Pathway Patients suspected of a haematological malignancy will be referred from across the network directly to the Paediatric Haematology team at Sheffield Children s Hospital. GPs and district hospitals within the network have been provided with information on when to suspect a haematological cancer and how to make a referral District hospitals will discuss patients suspected of a haematological cancer urgently with the paediatric haematology team at SCH and will be given advice on measures to stabilise the patient before transfer to SCH. Diagnosis and Treatment Pathway The approach to investigation of a suspected new or relapsing patient with acute leukaemia is described in Table 1. Investigations for the rarer sub-types are detailed in the specific guidelines referred to above and the relevant guideline should be consulted depending on the suspected diagnosis. Patient treatment should start on the basis of the diagnosis reached by an individual consultant haematologist who will ensure that the appropriate treatment regimen is allocated to the patient on chemocare. All patients with ALL and AML should be offered an opportunity to enter ongoing national or international clinical trials where available, but, regardless of trial entry, should be managed according to the standard treatment arms of current trial regimens. The diagnosis, treatment and risks of chemotherapy should be fully explained to the patient and the family before treatment commences. Written information should be provided and informed consent should be obtained for entry into the trial or administration of chemotherapy if the patient is being treated outside a trial. Where a trial is not available, patients should be treated according to national guidelines. Updated versions of these guidelines are in an intranet folder: H:\INFOAREA\Haemonc\CCLG guidelines\leukaemia. Once the results of all the relevant investigations are available, and no later than 2 weeks from presentation, the leukaemia MDT will agree a final diagnosis based on an integrated report. On rare occasions, this may necessitate a change to the patient s originally allocated therapy. SC(NHS)FT 2017 Page 2 of 15

3 The entirety of the patient s care will be co-ordinated and delivered by the leukaemia MDT at SCH except radiotherapy for which patients will be referred to Dr Kate Dunn at Weston Park Hospital. A key worker and named nurse will be allocated to the patient at the Team Planning Meeting. To avoid patients having to travel long distances for out-patient treatment: Some aspects of patient care such as replacement of NG tubes, administration of antimicrobial treatment instigated by SCH and occasionally initial management of febrile neutropenia might be undertaken at a DGH up to POSCU shared care level 1 only. A specified list of chemotherapy drugs, blood products, colony stimulating factors and intravenous anti-infective agents may be administered by the paediatric oncology outreach team in a domiciliary setting. Maintenance dose adjustment by telephone, based on local blood counts, will be offered to patients with ALL who are selected as suitable for this approach by the paediatric haematology MDT. The rare patient in whom standard therapy has failed may be referred to other centres for enrolment in phase I or II studies of experimental drugs. Local hospice teams will be asked for advice and support in the supportive and end of life care of children with incurable malignancies. SC(NHS)FT 2017 Page 3 of 15

4 PROBABLE ACUTE LEUKAEMIA PRE-TREATMENT INVESTIGATIONS (SEE ALSO UKALL 2003/AML 17 for trial specific investigations) A. Blood samples For an up to date summary of blood samples required, please refer to the research nurses document INV 01 B. Chest X-ray C. Bone Marrow Samples See Laboratory Sop For Details. LABORATORY INVESTIGATIONS AT RELAPSE OF ACUTE LEUKAEMIA A. Blood samples For an up to date summary of blood samples required, please refer to the research nurses document INV 01 B. Bone Marrow Samples See laboratory SOP SC(NHS)FT 2017 Page 4 of 15

5 TREATMENT General Hyperleucocytosis Patients with WCC > 100 x 10 9 /l are at risk of leucostasis resulting in respiratory failure and encephalopathy. The risk of leucostasis is higher in patients with AML and AT-CML than ALL. Consideration should be given to leucopheresis in patients with symptoms of leucostasis such as drowsiness, confusion, hypoxia (in the absence of focal chest pathology) and priapism. High dose hydroxycarbamide 20 mg/kg for up to 5 days is also effective in achieving rapid cytoreduction. Tumour Lysis Patients with high WCC and/or bulky disease are at high risk of tumour lysis on starting treatment. The risk is higher in lymphoid leukaemia, particularly Burkitt s lymphoma/leukaemia. These patients should receive hyperhydration, and Rasburicase. All other patients should receive hyperhydration and Allopurinol for 5 days. Provided the urine output is adequate alkalinisation of the urine is rarely indicated. For details of prevention, monitoring and management of tumour lysis syndrome, please refer to the Haematology/oncology guideline- tumour lysis on the subject. Blood components All blood components should be irradiated in patients who have received Fludarabine. Red cells should be transfused to patients with symptomatic anaemia or those with a rapidly falling Hb. Platelet transfusions should be used judiciously to prevent HLA sensitisation. A threshold of 10 x 10 9 /l in the absence of symptoms is safe in patients without additional risk factors such as fever, infection, coagulopathy or hypertension. In those with a higher risk of bleeding, the count should be kept at > 20 x 10 9 /l and in patients with APL (or those on heparin) at > 50 x 10 9 /l. FFP and cryoprecipitate should be given for severe coagulopathy after discussion with the haematology SpR or consultant. Patients with HLH, APL and high WCC AML are at high risk of intra-cranial haemorrhage and should receive aggressive blood component support to correct their coagulopathy. SC(NHS)FT 2017 Page 5 of 15

6 Acute Lymphoblastic Leukaemia (ALL) ALL Treatment Pathway (Except infants) Under 12 months? yes Interfant trial no B-ALL? yes CCLG B-NHL protocol no BCR-ABL? yes Ph positive ALL guideline no ALL Interim guideline/ukall 2011 Treatment modifications For Down syndrome patients In view of high treatment related mortality, DS patients will receive less intensive chemotherapy and additional supportive care. See current version of UKALL 2003 or 2011 for detailed recommendations. Eligibility for first remission allogeneic transplantation Allogeneic transplant in first CR is recommended for the following groups: 1. iamp21 with SER or day 29 MRD High Risk. 2. MLL rearrangement positive or hypodiploid < 44 with M2 marrow (>5% blasts) at day M3 marrow at day BCR:ABL positive, follow guidance within Philadelphia ALL protocol. 5. t(17;19) (E2A-HLF) positive The optimal timing of transplant, as recommended by the CCLG BMT Group, is on recovery from the consolidation phase of Regimen C at around weeks Where there is a delay beyond this time point, it is recommended that patients should receive standard maintenance therapy, rather than Cappizzi maintenance, during the interim. In due course, we may be able to identify patients with persistent high level MRD at the end of consolidation for further cyto-reductive therapy prior to transplant. SC(NHS)FT 2017 Page 6 of 15

7 Infant ALL Infants (age < 365 days) with ALL will be entered into the International inter-group trial Interfant 06 (and its successors). The current stratification and treatment allocation is as follows: Low risk (LR): High risk (HR): MLL germline MLL rearranged AND Age at diagnosis < 6 months (i.e. <183 days) AND WBC 300 x 10 e 9/L and/or prednisone poor response Medium risk (MR): MLL status unknown OR MLL rearranged AND age > 6 months OR MLL rearranged AND age < 6 months AND WBC < 300 x 10 e 9/L AND prednisone good response The standard (control) arm of therapy consists of the following blocks: induction, IB, MARMA, OCTADAD and maintenance. The experimental arm of therapy consists of the following blocks: induction, ADE, MAE, MARMA, OCTADA and maintenance. All low risk patients receive the standard arm. Medium risk and high risk patients are randomised to receive the standard or experimental arm (see Section 11.1). Medium risk patients with MRD levels of 10e-4 at the start of OCTADA(D) and all high risk patients are eligible for SCT, provided that the donor criteria as defined in the paragraph on SCT are fulfilled. HSCT should be undertaken after MARMA either before commencing OCTADA(D) or after receiving part of OCTADA(D). LR Induction IB MARMA OCTADAD MAINT MR Induction R IB MARMA OCTADAD MAINT ADE MAE MARMA OCTADA MAINT HR Induction R IB MARMA OCTADAD MAINT Allo SCT ADE MAE MARMA OCTADA MAINT SC(NHS)FT 2017 Page 7 of 15

8 Primary Refractory ALL Primary refractory disease is defined as an M3 marrow at day 29 of induction or M2 marrow at week 15 of Regimen C. Such patients have a poor prognosis and should receive one of the following off-trial regimens followed by an allogeneic transplant in CR1: FLAG-Ida FLAD Cyclophosphamide + Etoposide + Clofarabine (CYCLET) Nelarabine for T-cell disease Philadelphia Positive ALL Patients who are Philadelphia positive should receive UKALL 2003 Regimen B/C 4 drug induction and should be started on Imatinib or other Tyrosine Kinase inhibitor on the Ph status being known. Treatment subsequent to achieving CR will be discussed at the leukaemia MDT on an individual patient basis based on MRD response. Relapse ALL First relapse should be treated on the current UK relapse protocol (R3 at time of writing). Please refer to Haemopoietic Stem Cell transplant (HSCT) SOP Management of post-transplant relapse for patients who relapse after transplant. AML (Excluding Down syndrome and APL) New patients with AML, MDS-RAEB or granulocytic sarcoma (extramedullary AML) should be treated according to the national interim guidelines which have been adapted for local use (protocol on file).. APL and Down syndrome AML should be treated according to the specific CCLN guideline. SC(NHS)FT 2017 Page 8 of 15

9 Relapse AML Patients who relapse early (< 6 months from end of treatment) have a poor prognosis while late relapses are salvageable. Depending on which first line treatment the relapse occurred after, the patient should receive either FLAG or FLAD re-induction followed by an allogeneic transplant in second remission. Patients failing to achieve a complete remission with one or two re-induction course may still benefit from HSCT if they have shown chemo-sensitivity and are in a good partial remission (Blasts < 20%). Such patients should be offered a transplant with pre-conditioning cytoreductive therapy. See also relapse AML guideline, August Myelodysplasia including JMML The myelodysplastic syndromes are a group of disorders characterised by cytopenia in one or more cell lines, ineffective haemopoiesis, dysplasia in one or more cell lines and a high risk of transformation to acute leukaemia. Clonal cytogenetic abnormalities may or may not be present. Myelodysplasia (MDS) in children is rare and until recently has not been as well classified as in adults. MDS in children is often associated with constitutional genetic abnormalities, for example Down syndrome or neurofibromatosis type 1. It is also seen in congenital bone marrow disorders such as Fanconi Anaemia and Dyskeratosis Congenita.. Familial myelodysplasia/aml also occurs in the absence of other inherited conditions and may be associated with platelet storage pool disorders. Classification of Paediatric MDS Myeloproliferative/myelodysplastic - JMML (see below) - CMML Down syndrome disease - Transient abnormal myelopoiesis (TAM) - MDS/AML (the distinction is artificial) Myelodysplastic syndrome - Refractory cytopenia (<5% blasts) - Refractory anaemia with excess blasts (5-20% blasts) (RAEB) - Refractory anaemia with ringed sideroblasts Two entities are difficult to categorise within this Classification and should be Myelofibrosis and myelodysplasia Hypoplastic MDS SC(NHS)FT 2017 Page 9 of 15

10 Diagnostic Approach Careful History and Examination to include: A family history of leukaemia, any bleeding disorder, or any genetic disorder Previous cytotoxic or immunosuppressive therapy Previous treatment with cytokines, especially G-CSF Signs of a congenital or genetic disorders: Fanconi s anaemia Shwachman s syndrome Down syndrome Neurofibromatosis Type 1 Constitutional trisomy 8 Noonan syndrome Blood Samples Full blood count with differential and absolute monocyte count. Well stained blood films should be examined for the presence of abnormal morphology and to enumerate the blast count Fetal haemoglobin before any blood transfusion. HLA typing Virology It is important, particularly in infants with suspected JMML, to exclude a diagnosis of viral infections. Parvovirus, EBV and CMV may all mimic JMML. Bone Marrow Aspirate and Trephine Bone marrow aspirate for karyotype. Include iron stain in cytochemistry. Send sample to molecular laboratory for archiving. Trephine biopsy, with examination for abnormally localised immature precursor cells (ALIPS) and reticulin stain for fibrosis. A bone marrow aspirate is not necessary for diagnosis of DS-TAM if there are a sufficient number of peripheral blood blasts for immunophenotyping and karyotyping. Cytogenetics Clonal cytogenetic abnormalities can be detected in over 50% of children with MDS, the most common findings being monosomy 7 and trisomy 8. Deletion of chromosome 5q, a common finding in adult MDS, is rare in children. SC(NHS)FT 2017 Page 10 of 15

11 Treatment Patients with RAEB should be treated as AML. The vast majority of patients with Down syndrome transient abnormal myelopoiesis (TAM) do not require treatment. Patients with cardiac or liver failure should receive low dose cytarabine (10mg/m 2 /day for 5 10 days depending on response). Down syndrome MDS/AML should be treated according to the Down AML guideline. For all other types of MDS in children, the definitive treatment is an allogeneic transplant and a donor search should be commenced as soon as the diagnosis is confirmed. Pending transplant, patients with RA should receive extended phenotype matched blood and, if feasible, HLA matched platelets to reduce the risk of sensitisation. Patients with JMML may respond to low dose oral chemotherapy (Mercaptopurine mg/m2 po daily) or IV (cytarabine 100 mg/m2/day x 10 days +/- Etoposide 100 mg/m2/day x 5 days) and should receive it for disease control prior to transplant. IV treatment should be reserved for patients with progressive disease unresponsive to oral treatment. SC(NHS)FT 2017 Page 11 of 15

12 Ph-pos Chronic Myeloid Leukaemia For detailed recommendations on diagnosis and management, please consult the UK- CLWP childhood CML guidelines. The North Trent Cancer Network haemato-oncology guidelines should also be consulted for up-to date guidance on definitions of response to Imatinib and indications for use of second generation of TKI inhibitors (see table below). Imatinib should be given as first line therapy and patients who are Imatinib intolerant or resistant should receive second or third generation TKI inhibitors (Dasatinib or Nilotinib).. Leucopheresis and/or hydroxyurea may be required at diagnosis in patients with hyperleucocytosis. Allogeneic transplant should be discussed with patients who have a matched sibling or 10/10 matched unrelated donor, especially if they are Imatinib intolerant or resistant. Blood. 2006;108: SC(NHS)FT 2017 Page 12 of 15

13 Severe Aplastic Anaemia The following are selected extracts of the recommendations contained within the 2009 BCSH guideline for the diagnosis and management of Aplastic Anaemia which are particularly applicable to children. The full guideline should be consulted for diagnosis and management of an individual patient: Also refer to the 2012 version of the CCLG guideline which is on file. Diagnosis Careful history and clinical examination is important to help exclude rarer inherited forms. A detailed drug and occupational exposure history should always be taken. Any putative drug should be discontinued and should not be given again to the patient. All patients presenting with aplastic anaemia should be carefully assessed to: (i) confirm the diagnosis and exclude other possible causes of pancytopenia with hypocellular bone marrow (ii) classify the disease severity using standard blood and bone marrow criteria (iii) document the presence of associated PNH and cytogenetic clones. Small PNH clones, in the absence of haemolysis, occur in up to 50% of patients with aplastic anaemia and abnormal cytogenetic clones occur in up to 12% of patients with aplastic anaemia in the absence of MDS (iv) exclude a possible late onset inherited bone marrow failure disorder Treatment Supportive Care (i) Prophylactic platelet transfusions should be given when the platelet count is < 10 x 10 9 /l (or < 20 x 10 9 /l in the presence of fever). (ii) There is no evidence to support the practice of giving irradiated blood components except for patients who are undergoing BMT. However, recent guidance from the BCSH is that irradiated products should empirically be given to patients with aplastic anaemia receiving immunosuppressive therapy. (iii) Transfusion of irradiated granulocyte transfusions may be considered in patients with lifethreatening neutropaenic sepsis. (iv) The routine use of recombinant Humanised Epoetin in aplastic anaemia is not recommended. A short course of G-CSF may be considered for severe systemic infection that is not responding to intravenous antibiotics and anti-fungal drugs, but should be discontinued after one week if there is no increase in the neutrophil count. (v) Prophylactic antibiotic and antifungal drugs should be given to patients with neutrophil count < 0.5 x 109/l. Intravenous antifungal treatment should be introduced into the febrile neutropenia regimen early if fevers persist despite broad spectrum antibiotics. SC(NHS)FT 2017 Page 13 of 15

14 Definitive treatment Prednisolone should not be used to treat patients with aplastic anaemia because it is ineffective and encourages bacterial and fungal infection. Allogeneic BMT from an HLA identical sibling donor or > 9/10 matched unrelated donor is the initial treatment of choice for newly diagnosed patients if they have severe or very severe aplastic anaemia. Immunosuppressive therapy is recommended for children with non-severe aplastic anaemia who are transfusion dependent and those with severe or very severe disease who do not have a suitable donor. The standard immunosuppressive regimen is a combination of Anti-Thymocyte Globulin (ATG) and ciclosporin. ATG must only be given as an in-patient (see paediatric guideline for doses and schedule). Steroids are given in this situation to counteract the side effects of the ATG. Ciclosporin should be continued for at least 12 months after achieving maximal haematological response, followed by a very slow tapering, to reduce the risk of relapse. MMUD or haplo-identical family donor BMT may be considered when a patient has severe aplastic anaemia and has failed at least one course of ATG and ciclosporin. The optimal conditioning regimen for MUD BMT is uncertain, but currently a Fludarabine, non-irradiation-based regimen is favoured for younger patients. Myeloproliferative Disorders (Excluding Ph-pos CML) Essential Thrombocythaemia (ET), Polycythaemia Rubra Vera (PRV) and Primary Myelofibrosis (PMF) are exceptionally rare in childhood. In the absence of a JAK 2 mutation, the diagnosis rests on exclusion of secondary causes and the presence of features such as splenomegaly and marrow fibrosis. Familial cases often present in childhood and the diagnostic approach should include seeking a family history of the disorder and screening for known genetic mutations where possible. ET and PRV should be managed conservatively with drug therapy (aspirin, anagrelide, pegylated alpha-interferon and hydroxycarbamide) and phlebotomy respectively. Interferon is particularly effective in patients with severe pruritus. Patients with primary myelofibrosis should be planned for allogeneic transplant as soon as a donor is identified pending which they should receive a trial of steroids. Consult the CCLG guidelines on the matter for detailed recommendations on the diagnosis and management of myeloproliferative disorders in childhood. SC(NHS)FT 2017 Page 14 of 15

15 Haemophagocytic Lymphohistiocytosis (HLH) HLH should be suspected in any child with unexplained fever, liver failure and coagulopathy. The specific criteria for diagnosis are described in HLH 2004 which should be consulted for management of an individual patient. All patients (regardless of age, absence of family history and presence of viral trigger) should have samples sent to the immunology laboratory at GOS to screen for a genetic predisposition. Patients without a confirmed family history or genetic predisposition should receive the 8 week induction schedule of HLH 2004 and no further therapy. Patients suspected of having familial HLH on the basis of a family history or a mutation in an HLH predisposing gene should receive an allogeneic transplant as soon as possible after achieving a complete remission. SC(NHS)FT 2017 Page 15 of 15